Granulocyte Colony Stimulating Factor Pharmacokinetics After Single and Repeated Administration of Several Doses.
E. Pigeolet (1), F. Luedicke (2), S. Balser (2), G. Pinault (1) and P. Lowe (1)
(1) Novartis Pharma AG; (2) Sandoz Biopharmaceutical Development
Objectives: Granulocyte Colony Stimulating Factor (G-CSF) pharmacokinetics have a non linear dose and time dependent behavior, with its observed concentration-time profile markedly decreasing after repeated administration of the same dose. The non linearity has been attributed to the target mediated drug disposition and the increasing number of receptors located on the stimulated cells . The aim of the modeling analysis was to better understand and quantify the dose and time dependent non linearity of G-CSF pharmacokinetics.
Methods: We evaluated about 3000 plasma concentration-time records from rich sampling profiles of 112 healthy male and female volunteers. G-CSF was administered as repeated s.c. daily administration for one week of 2.5, 5 and 10 ug/kg doses and single i.v. dose (5 ug/kg). Pharmacodynamic data (blood neutrophil count) were available for the same time frame. Bayesian pharmacokinetic parameter estimates were obtained from simultaneous individual profile fits using NONMEM V.
Results: The structural model was a 2 compartment model with zero order absorption and an additional elimination rate constant from the peripheral volume of distribution (k20). Clearance, central and peripheral volume of distribution were increasing with time in a saturable way. A massive increase with time in the peripheral volume was observed from zero to about 14 L at steady state, whilst the central volume of distribution increased from about 2.5 to about 6 L. This is consistent with the large G-CSF induced increase of neutrophils and neutrophil precursors in the bone marrow as well as the release of neutrophils into the circulation. Clearance increased both with time and dose and k20 also increased with dose. It can be hypothesized that these changes are linked to an increased irreversible uptake of G-CSF due to the large number of G-CSF receptor positive cells after repeated administration. The bioavailability (F) was decreasing and the rate of distribution to peripheral tissues (Q) was increasing with decreasing doses. These changes are to be related to the saturable capture of G-CSF by its receptor.
Conclusions: The simultaneous modeling of i.v., s.c., single and repeated administration of several doses of G-CSF allowed to confirm and understand that its pharmacodynamics have a major impact on its pharmacokinetics.
 Kuwabara, T.; Kobayashi, S. and Sugiyama, Y. Pharmacokinetics and Pharmacodynamics of a recombinant human Granulocyte Colony Stimulating Factor. Drug Metabolism Reviews, 28 (4), 625-658, 1996.